© Borgis - New Medicine 4/2009, s. 109-113
*Calin Pop1, Marcel Pop2, Lavinia Pop1
Hyperglycaemia in Acute Coronary Syndrome: an unsolved problem in clinical medicine
1 „Vasile Goldis” Vest University, Faculty of Medicine, Arad, Romania
Head: Prof. Aurel Ardelean, rector
2 Semmelweis University, Faculty of Health Science, Budapest, Hungary
Head: Prof. Judit Meszaros, PhD
Acute or stress hyperglycaemia represents the transient elevation of the blood glucose level due to the activation of neurohormonal mechanisms in organisms exposed to stress. An abnormal prevalence of glycosuria in patients with acute coronary syndrome (ACS) had been reported as early as 1931 but it was only in 1975 that an abnormally high level of glycaemia following acute myocardial infarction (AMI) was noted to represent an aggravating factor affecting prognosis.
Acute hyperglycaemia induced hazards regarding ACS prognosis can be explained by the prevalence of insulin resistance syndrome in these patients, irrespective of the presence or absence of diabetes mellitus (DM), while clinical trials clearly highlight the fact that intensive glycaemic control reduces mortality rate in patients with a critical state of different illnesses, lessens the deterioration of renal function and cuts cardiovascular risk in patients with ACS. Glycaemic control in hyperglycaemia patients with ACS can be carried out by using a metabolic mixture containing a glucose-insulin-potassium mixture (GIK) independent of the glucose level status, or better by optimized insulin therapy. Proper achievement of the standardized protocol is imperative for obtaining optimal glycaemic levels and minimizing hypoglycaemia risks, especially in patients who develop ACS. Ongoing studies and trials will provide new elements and information that will improve the evolution and prognosis of patients with ACS and hyperglycaemia.
Acute or stress hyperglycaemia represents the transient elevation of the blood glucose level due to the activation of neurohormonal mechanisms in organisms exposed to stress.
The first data about the presence of hyperglycaemia in patients with critical illnesses were described by Claude Bernard in 1855. Since then a number of studies have demonstrated that in 5-30% of the cases these illnesses are accompanied by stress hyperglycaemia (1, 2).
Acute hyperglycaemia also induces imminent hazards regarding the evolution and prognosis of patients developing acute coronary syndrome (ACS), partially explainable by the increased prevalence of insulin resistance syndrome (3).
For better medical practice in this exciting field it is imperative that answers be found to a number of questions related to:
1. The prevalence and the risks induced by acute hyperglycaemia in ACS.
2. Whether elevated blood glucose is a marker or a mediator of more severe myocardial damage.
3. Whether acute treatment is going to have a significant impact or not; whether it can reduce short-term or long-term mortality and morbidity rate following ACS.
Prevalence and risks associated with acute hyperglycaemia in ACS
An abnormal prevalence of glycosuria in patients with ACS was reported as early as 1931, but it was only in 1975 that attention was directed to abnormally high glycaemia following acute myocardial infarction (AMI) representing an aggravating factor for prognosis (4, 5).
The influence of hyperglycaemia in patients free from diabetes mellitus
The first meta-analysis regarding the topic was published in 2000 by Capes et al. It comprised 15 cohort studies and clinical trials gathering 1856 patients free from DM, hospitalized for AMI. The relative risk (RR) of mortality was 3.9 times higher in patients with glucose>110 mg/dl (95% confidence interval [CI]:2.5-5.4) while in patients with glucose>144 mg/dl cardiogenic shock and congestive heart failure (CHF) it had a high prevalence. In their subsequent studies Wahab (6), Stranders (7) and Meier (8) successively demonstrated the existence of a larger necrotic area and a 4% higher mortality rate for each 18 mg/dl increase of glucose level in patients with AMI and admission hyperglycaemia, independent of the prior presence or absence of DM. In 2005 Ainla et al. (9) presented a study on 775 hospitalized patients with AMI in whom the mortality rate was 4 times higher in the subgroup with glucose level ≥ 200 mg/dl, 47% vs. 14%, compared with normoglycaemic patients. The Cooperative Cardiovascular Project (CCP), the most comprehensive study yet, evaluated 141,680 patients with AMI, and highlighted that depending on the admission glucose level (≥ 100 mg/dl up to ≥ 240 mg/dl) cardiovascular mortality rate increased from 13 to 77% at 30 days and 7 to 46% at 1 year.(10) Mortality risk was not influenced by the presence or absence of DM, but in patients with the same blood glucose level and free from DM the mortality rate showed a linear increase with glucose level ≥ 110 mg/dl. Mortality risk and CHF showed similar results starting with glucose level ≥ 200 mg/dl, irrespective of the diabetes status (11).
The influence of hyperglycaemia in patients with diabetes mellitus
The prevalence of DM in patients hospitalized for ACS is 20-25% but acute hyperglycaemia occurrence is more frequent and is present in 50% of them, even in those without a history of diabetes (3, 4, 6, 12, 13).
Isihara et al. (14) monitored 1,253 patients with AMI and DM who underwent emergency angioplasty (PTCA) and in whom the mortality rate was significantly higher (10% vs. 5%) as well as the procedural complications, having glucose level ≥ 200 mg/dl.
In a subsequent study Cao et al. (15) pointed out that mortality risk was 5 times higher in patients with blood glucose level ≥ 300 mg/dl and 2.6 times higher in those with blood glucose level ≥ 218 mg/dl, compared with blood glucose level ≥ 160 mg/dl, the reference value in the study.
DIGAMI [Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (16)] clinical trials CREATE–ECLA [Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment (17)] and HI-5 [Hyperglycemia Intensive Insulin Study in Infarction (18)] also highlighted a higher mortality rate (14-26%) in the long run in patients with AMI and DM.
The trials and the studies conducted so far suggest a different impact for acute hyperglycaemia in patients with ACS, depending on the presence or absence of DM. Thus some patients with hyperglycaemia but free from known DM could well have had an unidentified diabetes status, forming an extremely high risk group. It is also possible that a higher grade of severity of the disease or a higher level of stress resulted in the same level of hyperglycaemia in patients free from DM, although there is a tendency to administer intensive treatment to patients with hyperglycaemia and known DM.
Definition of admission hyperglycaemia
Hospital admission hyperglycaemia target values differ according to different studies. Moreover, there is no consensus about the definition of abnormal blood glucose values, methods to monitor blood glucose levels, the benefits of treatment, and the target values for blood glucose. A recent clarification on the subject matter has been issued by Deedwania et al. (19), who, irrespective of the metabolic status of patients developing ACS, suggest for hyperglycaemia an admission plasmatic glucose level ≥ 140 mg/dl, while for severe hyperglycaemia with a very high risk of poor outcome a value of ≥ 180 mg/dl is considered the lower limit. It is highly recommended to test plasma glucose levels compared to capillary glucose levels as plasma glucose levels tend to show 10% higher values (20).
Cardiovascular effects of acute hyperglycaemia in patients with ACS
In different studies hyperglycaemia was associated with a high incidence of coronary artery occlusions, with an unsatisfactory reestablishment of coronary artery blood flow type TIMI 0-2 [OR=2.6091.50-4.50)] and the occurrence and persistence of the so-called "no-reflow” phenomenon (21,22). Iwakura et al. published the results of a study carried out on 146 patients with AMI who underwent PTCA and among whom 52% of those having blood glucose level ≥ 160 mg/dl frequently suffered from the "no-reflow” phenomenon vs. 14% of normoglycaemic subjects. Isihara et al. (14) described a similar situation with a more frequent incidence of the "no-reflow” phenomenon in hyperglycaemic patients, 17% vs. 9%, as well as in those with known DM, 26% vs. 12%, whose blood glucose level was ≥ 200 mg/dl. In the same study hyperglycaemia was associated with more reduced values of ejection fraction (EF), 51% vs. 56%, associated with a delay of the reestablishment of contractile function, evaluated by the "Wall Motion Score Index” (delta WMS) in the study reported by Iwakura et al. (23). The afore-mentioned correlations are extremely important as the "no-reflow” phenomenon has been associated with a significant increase of mortality rate, while EF value is an important marker of long-term prognosis in patients with AMI (8, 24).
Acute hyperglycaemia determines endothelial dysfunction and inflammatory phenomena as a result of vasoconstriction. There is a prothrombotic state facilitated by the modification of plaquetary function and diminished fibrinolysis associated with the pro-inflammatory state induced by activation of κβ transcriptional intranuclear factor and metalloproteinase accumulation and the PAI-1 plasminogen activator inhibitor factor, favouring fissure and rupture of the atherosclerotic plaque. Insulin deficiency and excessive catecholamine release reduce ischaemic myocardium glucose utilization promoting glycogenosis with the stimulation of lipolysis and the increase in circulation of free fatty acids having pro-arrhythmogenic effects. Hyperglycaemia had formerly been associated with apoptosis and the reduction of collateral blood flow, the increase in necrotic area and the abolition of ischaemic preconditioning, associated with QT interval prolongation and a remarkable increase in arterial pressure in human volunteers with>270 mg/dl induced glucose level (25-32).
The relationship between all these physiopathological mechanisms seem to be ensured by the insulin-resistance phenomenon which in the SAN ANTONIO Heart Trial was associated with a 2.5 increase of mortality rate and major cardiovascular events even after multivariable analysis adjustment for the main cardiovascular risk factors (33).
The role and benefits of intensive hyperglycaemia management in ACS
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1. Bernard C. Lecons de physiologie experimentale appliqué a la medicine.Vol I.Balliere, Paris, 1855: 296-313. 2. Mc Kowen K, Malhotra A, Bistrian BR. Stress induced hyperglycemia. Crit Care Clin 2001; 17: 107-124. 3. Capes S, Hunt D, Malmberg K, et al. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic owerview. Lancet 2000; 335: 773-778. 4. Cruikshank N.Coronary thrombosis and myocardial infarction with glycosuria. BMJ 1931; 1:618-619. 5. Ravid M, Berkowicz M, Sohar E. Hyperglycemia during acute myocardial infarction: a six – year follow –up study. JAMA 1975; 233: 807-809. 6. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. ICONS Investigators. Is blood glucose a independent predictor of mortality in acute myocardial infarction in thrombolytic era? J. Am. Coll Cardiol.2002; 40: 1748-1754. 7. Stranders I, Diamant M, van Gelder RE, Spruijt HG, Twisk Jw, Heine RJ, Visser FC. Admission blood glucose blod glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med 2004; 164: 982-988. 8. Meier JJ, Deifuss S, Klamann A,Launhardt V, Schmiegel WH, Nauck MA. Plasma glucose at hospital admission and previous metabolic control determine myocardial infarct size and survival in patients with and without type 2 diabetes: the Langendreer Myocardial Infarction in Diabetic Patients Assesment (LAMBDA). Diabetes Care 2005; 28: 2551-2553. 9. Ainla T, Baburin A, Teesalu R, Rahu M. The association between hyperglycemia on admission and 180-day mortality in acute myocardial infarction patients with and without diabetes.Diabet Med 2005; 22: 1321-1325. 10. Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang I, Havranek EP, Krumholz HM. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulations 2005; 111: 3078-3086. 11. Zeller M, Steg P, Ravisy J, Laurent Y, Janin-Manificant L, L´Huillier I, Beer J, Oudot A, Rioufol G, Makki H, Farnier M, Rochette L, Cottin Y.Prevalence and impact of metabolic syndrome on hospital outcome in acute mzocardial infarction. Arch Intern Med 2005; 165: 1192-1198. 12. Norhammar A, Tenerz A, Nilsson G, Hansten A, Efendic S, Ryden L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002; 359: 2140-2144. 13. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: Important risk factor of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction:long term results from the Diabetes and Insulin – Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999; 99: 2626-2632. 14. Ishihara M, Kojima S, Sakamoto T. Acute hyperglycemia is associated with adverse outcome after myocardial infarction in the coronary intervention era. Am Heart J 2005; 814-820. 15. Cao JJ, Hudson M, Jankowski M, Whitehouse F, Weaver VD. Relation of acute and chronic glycemic control on mortality in acute myocardial infarction with diabetes mellitus. Am J Cardiol 2005; 96:183-186. 16. Malmberg K. DIGAMI (Diabetus Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Prospective randomised study of insulin intensive treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997; 314: 1512-1515. 17. Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, Paolasso E, Ahmed R,Xie C, Cazni K, Tai J, Orlandini A, Pogue J, Liu L. CREATE – ECLA Trial group. Effect of glucose-insulin-potassium infusion in patients with acute ST-elevation myocardial infarction: the CREATE – ECLA randomized trial. JAMA 2005;293:437-446. 18. Cheung NW, Wong WV, McLean M. The Hyperglycemia: Intensive insulin infusion in infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction.Diabetes Care 2006; 29: 765-770. 19. Deedwania P, Kosiborod M, Barett E, Cerriello A, Isley W, Mazzone T, Raskin P. Hyperglycemia and Acute Coronary Syndrome.Circulation 2008;117:160-1619. 20. Goldberg PA, Bozzo JE, Thomas PG, Mesmer MM, Sakhorova OM, Radford MJ, Inzucchi SE. "Glucometrics”: assessing the quality of inpatient glucose management. Diabetes Technol Ter 2006; 8: 560-569. 21. Timmer JR, Ottervanger JP, DE Boer MJ,van der Horst IC. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction.J Am Coll Cardiol 2005; 45: 999-1002. 22. Stone GW, Cox D, Garcia E. Normal flow (TIMI -3) before mechanical reperfusion therapy is an independent survival in acute myocardial infarction: analysis from the primary angioplasty in myocardial infarction trials. Circulation; 104:636-641. 23. Iwakura K, Ito H, Ikushima M. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction.J Am Coll Cardiol 2003; 41:1-7. 24. Brodie BR, Stuckey TD, Wall TC. Importance of time to reperfusion for 3-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction J Am Coll Cardiol 1998; 32: 1312-1319. 25. Kawano H, Motoyama T, Hirashima Q, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly supress flow mediated endotheluim dependent vasodilatation of brachial artery. J Am Coll Cardiol 1999; 34: 146-154. 26. Ceriello A. Acute hyperglycemia: a new risk factor during myocardial infarction. Eur Heart J 2005; 26: 328-331. 27. Young LH, Renfu Y, Russel R, Hu X, Caplan M, Ren J, Shulmann GI, Sinusas AJ. Low –flow ischemia leads to translocation of canine heart GLUT – 4 and GLUT-1 glucose transporters to the sarcolemna in vivo.Circulation 1997; 95: 415-422. 28. Kersten JR, Toller WG, Tesmer JP, Pagel PS, Warltier DC. Hyperglycemia reduces coronary collateral blood flow through a nitric oxid mediated mechanism. Am J Physiol Heart Circ Physiol 2001; 281: H2097-H2104. 29. Kersten JR, Schemeling TJ, Orth KG, Pagel PS, Warltier DC. Acute hyperglycemia abolishes ischemic preconditioning in vivo. Am J Physiol 1998; 275(pt2): H721-H725. 30. Ceriello A, Quagliaro L, D´Amico M, Di Filippo C, Marfella R, Nappo F, Berrino L, Rossi F, Giugliano D. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes 2002; 51: 1076-1082. 31. Marfella R, Nappo F, De Angelis L, Siniscalchi M, Rossi F, Giugliano D. The effect of acute hyperglycemia on QTc duration in healthy man. Diabetologia 2000; 43: 571-575. 32. Aljada A, Friedman J, Ghanim M, Mohanty P, HofmeyerD, Chaudhuri A, Dandona P.Glucose ingestion induces an increase in intranuclear factor kappa B, a fall in celullar inhibitor kappa B, and an increase in tumor necrosis factor alpha messenger RNA bz mononuclear cells in healthy human subjects. Metabolism 2006; 55: 1177-1185. 33. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 2002; 25:1177-1184. 34. Sodi-Pallares D, Testelli MR, Fishhelder BL, Bisteni A, Medrano GA, Friedland C, DeMichelli A. Effects of a intravenous infusion of a potassium -glucose-insulin solution on the electrocardiographic signs of myocardial infarction: a preliminary clinical report. Am J Cardiol 1962; 9: 166-181. 35. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruynincks F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically in the ill patients. N Engl J Med 2001; 345: 1359-1367. 36. Malmberg K, Ryden L, Webel H, Birkeland K, Bootsma A, Dickstein K, Efendic S, Fisher M, Hamstem A, Herlitz J, Hildebrant P, Mac Leod K, Laakso M, Torp-Pedersen C, Waldenstrom A. Digami – 2 Investigators. Intensive metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction: effects on mortality and morbidity. Eur Heart J 2005; 26: 650-661. 37. Svensson AM, Mc Guire DK, Abrahamsson P, Delborg M. Association between hyper- and hypoglycaemia and two year all- cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 2005; 26: 1255-1261. 38. Kadri Z, Danchin N, Vaur L, Cottin Y, Gueret P, Zeller M, Lablanche JM, Blanchard D, Hanania G, Genes N, Cambou JP: USIC 2000 investigators. Major impact of admission glycemia on 30 day and one year mortality in non diabetic patients admitted for myocardial infarction: results from the nationwide French USIC 200O study. Heart 2006; 92: 910-915. 39. Inzucchi S. Management of hyperglycemia in the hospital setting. N Engl J Med 2006; 155: 1903-1911.